DE69034007T2 - Inhalation device for dry powder - Google Patents

Abstract

An inhalation device for dry powder comprising a housing defining a chamber (11) for receiving a dose of powdered medicament in communication with a patient port (23) in the form of a mouthpiece or nasal adapter, the inhalation device additionally comprising: deagglomeration/aerosolisation means to deagglomerate and/or assist aerosolisation of said dose of powdered medicament, which means is operable by a patient-independent energy output source (13), detection means (31) to detect patient inspiration through the patient port (23), and, control means (19) to actuate said deagglomeration/aerosolisation means in response to detection of patient inspiration by said detection means.

Description

The invention relates to dry powder inhalation devices and in particular to an inhalation device in which a powdered dose of medication is nebulized or aerosolized in aerosol form for inhalation by a patient, the aerosolization not being dependent on the patient's inspiratory effort.

Asthma and other respiratory diseases have long been treated by inhalation of an appropriate medication. For years, the two most common and convenient treatment options have been inhalation of medication from a drug solution or suspension in a metered dose pressurized inhaler (MDI) or inhalation of a powdered medication, generally with an admixed excipient, from a dry powder inhaler (DPI). With growing concern about the close link between the depletion of the earth's ozone layer and emissions of chlorofluorocarbons, the use of these materials in pressurized inhalers is being questioned and interest in DPI systems has increased.

Known single and multiple dose dry powder devices use individual pre-measured doses, e.g. drug-containing capsules, which are inserted into the device prior to use, or have a built-in reservoir for loose powder from which sequential amounts of drug are transferred into a delivery chamber. While it is advantageous to use the action of the patient's breathing to both aerosolize powdered drug in the device and inhale the powder, thus overcoming the coordination problems necessary to synchronize inhalation with a drug delivery device, the efficiency of aerosolizing the powder particles depends on the work of inspiration of the patient, and in some cases a patient with breathing problems, such as an asthma attack, may not be able to produce sufficient inspiration to aerosolise and inhale the required dose of medication when the patient needs the medication most.

Agglomeration occurs when individual drug particles stick together in a semi-solid mass and requires increased inspiratory effort from the patient to separate drug particles and entrain them in the air stream. If the patient cannot provide sufficient inspiratory effort, the rate at which a drug penetrates the lower airways of the lungs decreases. Larger agglomerated drug particles (approximately 10 µm or larger) resulting from ineffective aerosolization are not stably entrained in the patient's air stream and deposit prematurely in the mouth/throat area, which can lead to undesirable systemic side effects, especially when strong drugs are administered.

Some inhalation devices have attempted to solve the problems associated with agglomeration and drug release; for example, US-A-3948264, 3971377 and 4147166 disclose inhalers for delivering drug in the form of a dry powder contained in a rupturable capsule. After breaking the capsule, the patient must operate an external device for operating a power source to supply the energy necessary to release the drug from the capsule while simultaneously inhaling through the device.

US-A-3948264 discloses the use of a battery-operated solenoid buzzer to vibrate the capsule and release the medication.

US-A-3971377 discloses the use of a propeller to generate an airflow that releases the drug. The power source includes an electric motor, a battery and an external switch combination or a threaded piston arrangement.

US-A-4147166 discloses the use of an impeller to generate sufficient air turbulence to release the drug. The power source comprises a battery-operated Motor, a compressed gas-powered turbine or a hand-operated differential gear train.

These devices are unsatisfactory because they can deagglomerate/aerosolize in an uncontrolled period of time prior to inhalation, and the patient may forget to activate the device before inhaling. Thus, the size and effectiveness of the dose absorbed by the patient's airways may vary between individual patients and/or individual administrations.

GB-A-898649 and 1479283 disclose dry powder inhalers with a manually compressed bellows or balloon to create a higher than atmospheric pressure in an air reservoir. When the patient inhales, a valve mechanism is actuated which releases the pressurised air into a chamber containing a dry powder capsule and from there into the patient's airways. Nevertheless, these devices remain patient dependent, although the energy used to aerosolise and deagglomerate the powder is not supplied by the patient's inspiratory effort. The degree of pressure applied to the balloon or bellows affects the energy supplied by the pressurised air, which in turn affects the type of powdered drug dose inhaled. For example, elderly, arthritic or very young patients may apply much less pressure than a more robust person. Similarly, for people suffering from asthma attacks, the devices are cumbersome and/or complicated when they are under a lot of stress. In addition, the patient must always remember to press the squeeze balloon or bellows before inhaling and must continue to apply pressure to this device while inhaling.

FR-A-2598918 discloses a device suitable for delivering 25 to 30 g of radiopaque particles into the airways of a patient over several breathing cycles. The device has means for detecting the breathing cycle and controls the gas and powder flow so that the powder supply is terminated on the exhalation cycle.

According to the invention, a dry powder inhaler is provided, which comprises:

a housing forming a chamber for receiving a powdered dose of medication,

a patient connection in the form of a mouthpiece or a nose adapter,

an inhalation channel connected to the chamber and the patient connection,

a deagglomerator that deagglomerates the powdered drug dose or helps aerosolize it, an electrically operated device that drives the deagglomerator,

a patient-independent energy output source that drives the electrically operated device,

a detector that detects the inspiration flow through the inhalation channel, and

a controller for actuating the deagglomerator in response to detection of the inspiratory flow by the detector, the detector having a movable vane positioned in the patient port or in the chamber, the vane being constructed and arranged to prevent exhaled air from reaching stored powdered medicament.

The invention provides a dry powder inhaler that can deliver reproducible powdered doses of medication in terms of both dose size and deagglomeration state by offering performance characteristics that are independent of a patient's inspiratory effort, manual dexterity, physical strength, or ability to coordinate separate movements, e.g., breathing and initiating a squeeze or breathing and pressing a button or lever, when administering medication.

The inhaler is made patient-independent by incorporating a patient-independent energy output source for deagglomerating/aerosolizing medication and a breath actuation mechanism that responds to the inspiration flow and can synchronize medication release with inhalation. To receive a dose of medication, the patient simply inhales through the mouthpiece. The detection device detects the patient's inhalation and triggers the deagglomerating/aerosolizing device. which operates in such a way that it ensures effective aerosolization of the medication in the air stream. The energy required to operate the deagglomeration/aerosolization device during inspiration is independent of the patient's inspiratory effort and does not require any manual effort from the patient when administering the medication.

The inhalation devices of the invention may be single dose, requiring the insertion of a new dose after each successive use, or multidose, with the device containing several such doses. Generally, single doses of medication are contained in a rupturable capsule, which is normally inserted into the device when needed. Typically, the patient carries several such capsules in a blister pack. Multidose devices may also use capsules, but are more likely to have a reservoir for powdered medication and a powder transfer member for delivering a dose of medication into the chamber.

Typically, the capsules are formed of gelatin, although any suitable material may be used which is both inert to the drug contained within and capable of being satisfactorily punctured or otherwise cleaved. The capsule may be manually opened or broken by the patient prior to insertion into the device, or the sealed capsule may be broken during or after insertion into the device.

In one embodiment, the capsule is securely housed in a enclosure within the aerosolization chamber and is punctured in situ by one or more retractable piercing members, which are normally spring loaded and actuated by opening the mouthpiece prior to inhalation.

Alternatively, a multi-dose inhaler may comprise a reservoir for loose powder and a length or area of suitable material forming, in part or in whole, a powder transfer member, the member moving past or through a storage chamber containing the powder medicament so that a controlled amount of the powder is transferred to the surface of the material.

The material and its powder coating then move into the aerosolization chamber of the device, where a certain physical force is applied to the material to release a fixed proportion of the powder as an aerosol suitable for inhalation.

Preferably, the powder transfer part comprises a material with suitable surface characteristics to enable it to be evenly coated with powder. The part may comprise a number of ancillary parts, e.g. for support and stiffening, or it may consist solely of the transfer material itself. Examples of materials that may be suitable include nonwoven fiber materials, molded filament materials, e.g. "Scotchmate" or "Dual-Lock" commercially available from Minnesota Mining and Manufacturing Company; microporous materials, microgrooved polymeric materials, or textured surface materials having small surface grooves or depressions formed in their surface with a typical size of < 500 µm deep and no more than 500 µm in at least one other dimension. Preferably, the physical form of this powder transfer material would be a tape or disk, although other forms may be used, e.g. E.g. a thread or a string or simply a surface of material with a certain shape, e.g. a rectangle.

The manner in which the material moves between the powder storage chamber and the area of the device where aerosolization takes place is related to its physical shape. For example, a tape, thread or cord may be preferably used for straight-line transport through or past the storage chamber, while a disc may preferably be rotated so that a certain part of the disc is in the storage chamber and a second part is in the aerosolization chamber. A fixed area of powder transfer material is then rotated from the filling station into the aerosolization chamber. Any specific part of the surface of the powder transfer material may be used once or more than once.

The application of powder from the reservoir to the transfer material can be accomplished by any suitable means. For example, the transfer material can move through the powder or pass under or over it. The transfer part can itself form a boundary of the powder reservoir. The powder transfer material can pass over or between brushes, rollers, scrapers, etc. or other metering devices to control or vary the amount of powder applied to it. For example, microgroove material could be evenly coated with powder (thus precisely controlling the dose) by scraping powder into the grooves on its surface to fill them. For other materials, the dose can be determined by carefully controlling the interface parameters between the transfer material and the powder reservoir, e.g. by controlling the forces under which they are brought into contact.

An example of an arrangement suitable for use with the devices of the invention is disclosed in EP-A-069715, wherein the powder reservoir comprises a storage chamber and the transfer part comprises a horizontally oriented perforated membrane mounted on a rotatable manoeuvring unit. Thus, the storage chamber and the membrane are arranged to be displaceable in relation to each other between a first position in which medicament is introduced into the perforations in at least part of the membrane surface and a second position in which the membrane surface thus loaded is displaced by rotation into the aerosolization chamber before energy is supplied for deagglomeration/aerosolization.

Other problems sometimes arise because it is necessary to provide a sufficient amount of powder (e.g. hundreds of micrograms) to overcome problems associated with accurately transferring measured small amounts of drug into a capsule or onto a transfer device. For example, with strong drugs, an excipient is usually added to the drug, e.g. lactose powder, to increase the amount of powder to be measured. Excipients are undesirable because they are generally too large to be inhaled by themselves, and yet they can retain adherent drug particles which thus become deposited in the mouth and throat. In addition, drug carriers cause dry mouth and can be responsible for dental caries. Therefore, in a most preferred embodiment, the drug source comprises a preloaded carrier as disclosed in our co-pending GB-B-8909891, filed April 28, 1989, and PCT application US90/02412 (WO-A-9013238), filed on the same date.

Devices utilizing an elongated carrier provide a simple, effective dry powder inhaler capable of delivering numerous even doses of medication to a patient. The device is simple to use and does not require the patient to insert medication capsules or rely on a separate medication reservoir to load the device for use. The medication is pre-applied to an elongated carrier, sections of which are fed sequentially into the medication delivery chamber. Conveniently, the elongated carrier can be loaded onto a spool (similar to photographic film) or into a cassette (similar to an audio cassette). The elongated carrier can have any length to width ratio, but is preferably greater than 5:1, more preferably greater than 10:1, and even more preferably between 100:1 and 1000:1.

The preloaded elongated carrier may take a variety of forms, but is preferably a tape, web, belt or cord. The powdered medicament may be held on the carrier by electrostatic attraction, van der Waals forces, physical attraction, mechanical bonding, wedging, or by a covering layer or a coating layer of the same carrier when the carrier is wound, etc. One or more surfaces of the carrier and optionally the carrier interior may be configured to assist in retaining the powder particles.

The carrier may be made of one or more of a variety of natural and synthetic materials, such as polyethylene, polypropylene, polyester, polytetrafluoroethylene or a copolymer thereof and cellulose. The materials may be in the form of nonwoven fibre materials, loosely woven materials or fabrics, materials with a surface pile, films, microporous materials, microgrooved materials, cords of twisted fibres or any material or composite of more than one material having small surface grooves, recesses, gaps, openings or embossed surface structures with a typical size < 500 µm in depth or height and more than 0.1 µm in at least one other dimension to retain the powder particles.

Preferably, a microgroove material comprises a tape, sheet or belt having one or more grooves on the support surface 10 to 500 µm wide and 10 to 500 µm deep, but generally the grooves may have dimensions at least an order of magnitude larger than the largest particle. The microgrooves may be partially or completely filled, the latter facilitating a dose control device when the material is applied under uniform conditions. The microgrooves need not be continuous or straight and may extend in one or two dimensions.

Preferably, a microporous material comprises a tape, sheet or belt with pores of 0.1 to 100 µm diameter, which may be randomly oriented. At least a portion of the pores must be on the outer surface. A preferred pore formation process utilizes solvent extraction of oil droplets dispersed in a support material film.

Another embodiment of a microporous material is made by a laser drilling process and has a tape, sheet or belt with pores of 1 to 100 µm diameter, preferably 20 to 50 µm, in at least one surface.

A nonwoven material may be of any suitable shape, but preferably is in the form of a tape, web or belt. It may contain any type and shape of fibers, although fibers of 0.1 to 100 µm diameter are preferred and 5 to 20 µm diameter are most preferred. Fibers may be of any suitable length, but preferably 1 to 100 mm. The nonwoven material may be formed by any suitable process, e.g. combing or brushing, depositing fibers from a transport gas or liquid, or extruding and blowing microfibers. The fibers may be bonded over at least part of the surface of the material, e.g. by heat fusing, to increase the mechanical strength of the material. Such a bond may most conveniently be at the belt or web edges and may conveniently be formed as part of a process for slitting the belt e.g. by a laser or thermal slitting device. In addition, the material may be perforated or embossed and may optionally be permeable to air.

The nonwoven material may use a mixture of fiber compositions or forms. In a preferred embodiment, bicomponent fibers with a readily fusible outer component are used. Such fibers can easily bond together to prevent or minimize fiber detachment. In another preferred embodiment, spunbond fibers are used to achieve the same goal using their greater fiber length. In a third embodiment, continuous reinforcing filaments may lie in the plane of the material to anchor the fibers and provide additional mechanical strength to the material. In a fourth embodiment, paper-like nonwoven materials formed by fiber deposition from a liquid may be used because they have additional strength compared to other materials and may result in less fiber detachment due to increased fiber entanglement.

The tape, web or belt may contain reinforcing threads in the plane of the material and/or a backing layer, e.g. a metal foil such as aluminum or a polymer film or a combination thereof. A metalized backing layer is advantageous when the carrier is stored as a roll, as it forms a conductive surface that can reduce drug transfer from the coated surface to the uncoated surfaces. The backing layer may Have perforations so that an air stream can flow through the actual carrier material.

The carrier may be loaded by brushing, scraping or spreading a powdered drug onto the carrier surface.

Alternatively, the carrier may be charged by evaporation from a drug suspension, by precipitation from a drug solution, or by deposition from an aerosol, e.g. by spraying, impact, collision, diffusion, or electrostatic or van der Waals attraction. For example, the drug particles may be deliberately given an electrical charge immediately before deposition. The technique of deposition of a charged aerosol may be complemented by the use of a carrier with an inherent electrostatic charge. Ideally, the carrier should be an insulator, e.g. polytetrafluoroethylene, which can hold the charge; alternatively, the carrier may contain an artificial charge due to the presence of electrets. In general, the choice of deposition technique depends on the properties of the carrier material used.

Coating may involve the use of stencils, matrices, etc. to allow individual areas of the carrier medium to be coated with individual doses. The drug may be deposited in patterns to avoid contact between the drug and any ink markings on the tape.

A preferred carrier for use in the invention is disclosed in US-A-5192548 (Attorney Docket No. 45128 USA 1A) of even date. This patent application discloses a flexible sheet having a plurality of discrete depressions in at least one surface, each of the depressions having a depth of about 5 to 500 µm but less than the thickness of the sheet and an opening on the surface of the sheet of about 10 to 500 µm in transverse dimension, a substantial number of the depressions being at least partially, preferably at least 75%, filled with micronized medicament, and the area of the sheet surface between the wells is essentially free of micronized drug.

The flexible sheeting may have a substantially regular array of depressions or micro-pits formed in the top surface of a polymeric material layer. Generally, the depressions are frustoconical in shape, but may alternatively have any suitable configuration for containing micronized drug, including, but not limited to, generally truncated pyramids, hemispheres and tetrahedrons, and other geometric or non-geometric configurations. Currently preferred depressions have a sidewall angle of about 15 to 20 degrees from vertical. The array of depressions may take any shape or pattern and need not be regular (i.e., the array may appear irregular).

Generally, the depressions have a depth of about 5 to 500 µm and an opening on the surface of the sheet material of about 10 to 500 µm transversely relative to the main axis of the opening. For depressions with generally circular openings, e.g. truncated cones or hemispherical parts, this main axis is actually the diameter of the circular opening. Preferred depressions have a depth of about 10 to 100 µm and an opening (e.g. diameter for truncated cones or hemispherical parts or similar) on the surface of the sheet material of about 50 to 200 µm. Generally, the depressions have spacings of about 20 to 200 µm, preferably about 50 to 200 µm. Preferably, the number of depressions is about 500 to 15,000 per cm² of sheet material. The volume of each well and the spacing or number of wells will depend on the strength of the drug and the area of sheeting intended to represent a single dose of the drug. Preferably, the sheeting has a substantially uniform volume of wells per unit area.

Furthermore, the web material can have a support layer, e.g. made of paper. The polymer material layer can be laminated, melt bonded or extruded onto the carrier layer. Other support layers can be made of nonwovens or polymers, e.g. polyester.

The polymer material layer may comprise any suitable polymer, e.g. polyethylene, polypropylene, polyester, polytetrafluoroethylene, and cellulose. Polyethylene is preferred. Typically, the polymer material layer is about 25 to 100 µm thick.

The sheet material can be made of a single material, e.g. polypropylene. In such an embodiment, the support layer is not required, since the sheet material is sufficiently intact and durable even without the support layer.

A preferred sheeting is made using polyethylene coated kraft paper from Schoeller Company. The depressions are deep enough not to form pores extending through the entire thickness of the sheeting.

Generally, the top surface of the sheet is coated with micronized drug such that the recesses are at least partially filled, followed by general removal of excess drug from the top surface of the sheet in areas of the sheet between the recesses, e.g., by scraping, optionally followed by rolling between silicone pads.

Since the packing density of the micronized drug in the wells can affect the shape and amount of drug released from the sheet material during the aerosolization process, care should be taken to ensure that the packing density remains substantially uniform throughout the coating process.

The aperture and depth dimensions and spacing of the recesses affect how much micronized drug the sheeting can carry per unit area for a given level of drug compaction during loading or coating. Furthermore, the recess depth can affect the degree to which the drug is released from the sheeting and its relative agglomeration or deagglomeration state. Using salbutamol sulfate with a mean particle size of 1.7 µm and for single impacts of inhaler-suitable strength on sheeting areas of about 2 to 10 cm2, the following was observed: The percentage of drug retained on the sheeting or tape decreases with increasing depth, being about 95% at 14 µm, about 60% at 28 µm, and about 35% at 45 µm. Furthermore, the respirable fraction (i.e., the percentage of drug present in particles with an aerodynamic diameter equal to or less than about 6.4 µm) similarly decreases with increasing cavity depth, being about 65% at 14 µm, about 30% at 28 µm, and about 10% at 37 µm. These two trends result in the total drug fraction released in respirable-sized particles remaining generally similar for the cavity depths studied (being about 5 to 15% of the total drug).

Depressions can be formed in the sheet material by any suitable technique, e.g., creating micro-indentations through a photolithographically patterned magnesium alloy plate or other micromachined plate. Other conventional techniques that can be used are optical imaging or laser imaging.

As an illustrative example, a sheet was prepared with a photolithographically produced etched magnesium alloy pattern plate having an array of pyramidal protrusions in the number of about 1550 per square centimeter, wrapped around a steel roller. The roller was heated with oil to about 225ºF. The polyethylene surface of polyethylene coated kraft paper (commercially available from Schoeller Company) was pressed against the surface with a rubber or steel press roller, which was also heated with oil and pressed against the patterned roller.

It is preferred that the drug used has a strength by which a single dose can be applied to the sheeting in an area of less than about 25 cm² and preferably less than about 5 cm². More preferred is a sheeting which delivers a drug in such a manner and from a such that between 0.25 and 2.25 cm², most preferably between 0.5 and 2.0 cm² of sheeting material contains a single dose. In other words, since a sheeting material of the invention can conveniently carry between about 10 and 150 µm of medicament per cm², the strength of the medicament is preferably such that a single dose can be carried on the above 0.25 to 2.25 cm² of sheeting material.

In the most preferred embodiment, the carrier is in the form of a tape. The type of carrier determines the method of transport between a storage facility and the chamber in which aerosolization occurs. In a preferred embodiment, the preloaded carrier is stored wound on a spool contained in a cassette. A tape, sheet or belt can be used to give the storage carrier other configurations, such as folding it in a zigzag pattern, which has the advantage that the drug-carrying surfaces touch each other, thus preventing net drug transfer during storage. Each fold can form a unit dose of the drug. Folding along the long axis of the tape, called a hybrid fold, can also prevent undesirable net drug transfer. Strings or threads can be conveniently stored as spools.

The device includes means for advancing the elongate carrier through the chamber to expose successive surfaces of the carrier for drug release as the patient inhales. The advancing means may take a variety of forms depending on the type of elongate carrier and whether the exposed carrier surfaces are to remain in the device. For example, tapes, webs and belts may have a series of apertures into which one or more spiked guide wheels or rollers engage, similar to those of a camera or printer. Alternatively or additionally, the carrier may be wound on a take-up spool, rotation of the spool causing the carrier to advance, directly or via a drive belt. In addition, the device may include means for tensioning or otherwise Keeping the exposed surface of the wearer in the chamber while the patient inhales.

Preferably, the elongate carrier can be advanced into the chamber prior to the patient inhaling, or the carrier can be advanced into the aerosolization chamber during inhalation to protect the powdered medicament from premature exposure. For example, in one embodiment of the inhaler, an unexposed carrier surface is rapidly advanced into the chamber upon actuation and rapidly decelerated or brought to a sudden stop and preferably subjected to an impact which imparts sufficient energy to the medicament particles to move from the carrier into the airstream.

In the preferred embodiment of the invention, the elongate carrier is stored in a cassette before and after exposure. The cassette may comprise one or preferably two spools together with idler or other rollers and may have an exposure frame positioned in the chamber through which the carrier is advanced. The cassette may be removable to allow a new cassette to be reloaded into the device. However, it is not essential that the exposed carrier surfaces remain in the device and spent carrier may be discharged from the device through a slot in the housing, after which the patient may take care of disposal, optionally with the aid of a cutting edge. This arrangement is particularly suitable for a tape carrier with transverse perforations to facilitate tearing off spent carrier.

The predetermined area of the carrier to be exposed in the chamber may be 0.1 to 20 cm², and preferably 2 to 3 cm². The drug may be applied to one or more surfaces of the carrier and/or enclosed in interstices in the carrier to allow a dose of 5 µm to 1 mg to be entrained in the air stream generated during inhalation. It is not essential to entrain all of the drug in the air stream in this way, provided that the amount of drug released from the predetermined area is reproducible in successive applications.

In addition, the device may have a facility to display one or more of a variety of parameters, e.g. readiness for use, remaining content, drug type, etc.

The display may simply warn that the drug supply is running low, or it may provide more detailed information, such as the current dose number or the number of doses remaining. In addition, the display may provide information on the drug's manufacturing or expiry date, as further examples. For treatments to be given regularly at set times, the display may show the day of the week, date and time of the scheduled administration. Conveniently, the information shown on the display may be marked on the tape or tape cover by any suitable method, whether printing, notching, etc. The tape area in the display need not correspond to that used to release the drug at that time.

Dry powder inhalation devices with an elongated carrier can have numerous advantages over state-of-the-art devices. These include:

1. An inhaler with dose control by powder removal from a fixed, uniformly coated band area has more consistent doses and a more consistent respirable fraction than state-of-the-art devices. High respirable fractions are desirable because they allow a high proportion of drug to be inhaled into the lungs and provide therapeutic benefit and because they reduce the proportion of drug that causes undesirable systemic side effects after swallowing from the oral and pharyngeal region.

2. The inhaler allows smaller amounts of undiluted potent drugs (typically less than 200 ug), e.g. corticosteroids, to be administered accurately than is currently possible. This eliminates the problems associated with the use of excipients.

3. The storage of pure powdered medication on the surface of a tape is suitable for dose adjustment or to use different medicines with minimal effort and without reformulation.

4. The inhaler is suitable for use with a wide variety of different medications.

5. By controlling the tape or web dimensions, a precise number of doses for inhalation can be stored in the inhaler.

6. The belt may be marked so that the inhaler can register the exact number of doses remaining or alternatively a counter mechanism may be driven by the belt feed mechanism.

7. The amount of drug inhaled and the degree of particle deagglomeration do not depend on the patient's inspiratory effort, thus eliminating the need for hand-lung coordination while providing a consistent dose at all times for all patients regardless of lung function.

8. Since aerosolization/deagglomeration of the drug does not depend on the speed of the airflow, patients can learn to inhale slowly, unlike with most dry powder inhalers, which reduces unwanted drug impact in the back of the throat.

In general, the means for aerosolizing/deagglomerating the drug will cause drug release from the dose source and particle agglomeration to be broken up by applying mechanical energy that is independent of patient effort. The method used may be one or more of a number of suitable physical methods, e.g. impact or shaking, brushing or scraping, or the use of air turbulence created by a propeller or impeller. The choice of which method to use will vary depending on the drug source, e.g. capsule, elongated carrier or powder reservoir and transfer member. Thus, while the invention is illustrated by using an elongated carrier, the general principles may also be applied to inhalers using capsules, transfer members, etc.

The drug release device serves to weaken the bond between the drug particles and the carrier and breaks up particle agglomerates mechanically, e.g. by impact, shaking, gas flow, etc., or electrostatically. The energy supply for mechanical deagglomeration/aerosolization can be achieved by:

(i) an impact device, such as one or more spring-loaded impact hammers, which impact one or more times on the exposed portion of the beam;

(ii) a brushing or scraping device with rotary or reciprocating motion on the exposed carrier portion, e.g. spring-loaded or electrically driven rotary members with protruding bristles or flaps; dragging the carrier over uneven surfaces, e.g. an idler gear or a surface bearing a plurality of embossed structures with similar surface features, or dragging the carrier over an edge or corner with a small radius of curvature so that the drug-bearing surface is sharply convexly curved;

(iii) compressed gas flowing past, through or impinging on the carrier from a compressed or liquefied gas source;

(iv) a vibrating device for causing the exposed support portion to vibrate, generally in the frequency range of 5 to 250,000 Hertz; the vibrations may be derived electrically or piezoelectrically, e.g. using the piezoelectric properties of polymeric PVDF2; electromagnetically, e.g. with an electromagnetic vibrating arm or pin, or mechanically, e.g. with rotary cams or gears, whereby the cam or wheel may rotate rapidly in contact with the support or the support may move over the cam or wheel.

The drug release efficiency can be increased if the carrier and/or drug particles have an intentional charge by reversing the polarity of the carrier during aerosolization and inhalation.

The deagglomeration/aerosolization device is triggered in response to the patient's inhalation to prevent the patient from inhaling and activating the Medication release mechanism must be synchronized. Detection of airflow is conveniently achieved with a movable vane positioned in the chamber or patient port, movement of the vane actuating the release mechanism. The vane may be spring loaded to return to an initial position. The vane is designed to prevent a patient from exhaling through the device, preventing exhaled air from reaching the stored medication, thereby avoiding problems associated with moisture ingress and agglomeration. Another such sealing device may also be used.

A control system is provided which activates the aerosolizing/deagglomerating mechanism in response to the detection of a developing airflow through the device. The control system may be an electrical or mechanical coupling between the flow sensor and a means for aerosolizing, the selection of which depends on the type of flow sensor and type of aerosolizing/deagglomerating mechanism to be used. For example, in a device having a movable vane for detection purposes, its displacement may cause a microswitch or reed switch to close, completing a circuit with a battery to power an electric motor which, for example, rotates a propeller or powers a solenoid buzzer.

Suitable medicaments for use in the invention include any drug which can be administered by inhalation and which are solids or can be incorporated into a solid carrier. Suitable medicaments include those for treating respiratory disorders, e.g. bronchodilators, corticosteroids and asthma prophylactics. Other drugs may be used, e.g. anorectics, antidepressants, antihypertensives, antineoplastics, anticholinergics, dopaminergics, narcotic analgesics, adrenergic beta-blockers, prostaglandins, sympathomimetics, tranquilizers, steroids, vitamins and sex hormones.

Exemplary medicines include:

Salbutamol, Terbutalin, Rimiterol, Fentanyl, Fenoterol, Pirbuterol, Reproterol, Adrenalin, Isoprenalin, Ociprenalin, Ipratropium, Beclomethason, Betamethason, Budesonid, Dinatriumcromoglycat, Nedocromil-Natrium, Ergotamin, Salmeterol, Fluticason, Formoterol, Insulin, Atropin, Prednisolon, Benzphetamin, Chlorphentermine, amitriptyline, imipramine, cloridine, actinomycin C, bromocriptine, buprenorphine, propranolol, lacicortone, hydrocortisone, fluocinolone, triamcinclone, dinoprost, xylometazoline, diazepam, lorazepam, folic acid, nicotinamide, clenbuterol, bitolterol, ethinyloestradiol and levenorgestrel. Medicines may be formulated as a free base, one or more pharmaceutically acceptable salts or mixtures thereof.

The powdered drug may be finely micronized by stepwise repeated grinding or a closed loop grinding system and is preferably in the particle size range of 1 to 10 µm. The drug may comprise one or more drugs having one or more specific shapes and may contain one or more physiologically acceptable or inert drug carriers. The drug particles may have a coating of a surfactant, e.g. a perfluorinated surfactant, or other surfactants, e.g. Span 85, oleic acid, lecithins.

The invention is described below with reference to the accompanying drawings.

Fig. 1 is a section through an inhaler according to the invention with a battery-operated shaking device for deagglomeration/aerosolization.

Fig. 2 is a section through an inhaler according to the invention with a battery-operated impact device for deagglomeration/aerosolization.

Fig. 3a to 3d illustrate an inhaler of the invention with a spring-loaded impactor for deagglomeration/aerosolization. Fig. 3a is a front view, Fig. 3b a rear view and Fig. 3c a plan view of the Exterior of the device. Fig. 3d is a cross-section through the inhaler along the AA axis.

Fig. 4a and 4b show an inhaler of the invention with a battery-operated rotary brush for deagglomerating/aerosolizing medication.

Fig. 5 is a section through an inhaler according to the invention with a battery-operated shaking device for deagglomeration/aerosolization.

Referring to Fig. 1, an inhaler 1 for use with powdered medicament enclosed in a rupturable capsule comprises a housing 3 defining interconnected compartments 5 and 7, a capsule receiving enclosure 9 and an aerosolizing chamber 11. Compartment 5 contains a battery 13 located in mounting tabs 15 and accessible to the patient for replacing an empty cell. Compartment 7 contains a solenoid vibrator 17 which is in electrical communication with a control mechanism 19 and a microswitch 21 and completes an electrical circuit with the battery 13. When the device is not in use, the microswitch 21 is open so that the above circuit is not completed, preventing the vibrator from being operated.

The aerosolizing chamber 11 communicates with a patient port 23 which is provided with a mouthpiece 25, although the device may be provided with a nose adapter (not shown) or alternatively the device may be provided with both. The enclosure 9 communicates with the outside atmosphere via an inlet 27 and with the aerosolizing chamber 11 via integral air slots 29 so that a flow of air through the device from the outside atmosphere can be generated by patient inhalation at 23. A vane 31 is pivotally mounted about a point 33 and is displaceable when a flow of air is generated by patient inhalation through the device. Displacement of the vane 31 causes an interaction between a vane part 35 and the microswitch 21 which temporarily closes the switch 21, thereby completing the above circuit and operating the agitator 17. In addition, the vane part 35 serves to prevent the Wing 31 rotates fully out of the patient connection 23. The wing is spring-loaded to return to the starting position when the patient air flow stops, causing the microswitch 21 to open again and thus interrupt the circuit.

In use, a patient inserts a capsule 37 into the port 27, which is provided with one or more cutting or piercing members 39 so that the integrity of the capsule is destroyed upon insertion. Alternatively, the patient may manually break the capsule open prior to insertion. The enclosure 9 is suitably configured so that the capsule rests very close to a piston rod 41 of the vibrator 17. By oscillating the piston rod against the capsule after the vibrator is actuated, medicament particles of respirable size are deagglomerated and released from the capsule, whereupon they are drawn into the developing air stream. The vane 31 ensures a unidirectional air flow from the outside atmosphere via the port 27 to the patient connection 4 or 23 by being displaceable only in a forward direction. A stop 44 prevents movement in a backward direction when the patient inhales. Except for the connection necessary for operation of the buzzer and vane, the compartments 5 and 7 may be substantially sealed from the enclosure 9 and chamber 11 to prevent the ingress of powdered medicament which may affect the operation of the device.

Referring to Figure 2, an inhaler suitable for use with a pre-loaded elongate medicament carrier comprises a housing having a body portion 45 and a lid 47 hinged at 49 and movable between an open position (shown) and a closed position. When the device is not in use, the lid minimises contamination from ingress of dirt or moisture. The body portion 45 defines interconnected compartments 5 and 7 and an aerosolisation chamber 11. The compartment 7 contains an integral carrier supply spool 51, guide rollers 53 engaging the carrier and an integral carrier take-up spool 55 so that a carrier 57 can be sequentially moved over an exposure frame 59 in connection with with the aerosolizing chamber. A dose advancement device is not shown but may comprise mounting the take-up spool on a drive shaft extending through the housing which can be manually rotated by means of a knurled knob. Alternatively, a suitable gear train may be connected to the take-up spool and a recessed dose advance wheel or lever located in the housing to effect dose advancement. In addition, the compartment 7 contains a control mechanism 19, a deagglomerating/aerosolizing device comprising a solenoid 61 and a percussion hammer 63, and a reed switch 65 which completes an electrical circuit with a battery 13. When the device is not in use, the reed switch 65 is open so that the above circuit is opened, preventing operation of the solenoid.

In use, an unexposed portion of the carrier 57 is advanced by the patient toward the exposure frame before the lid 47 is moved and inhaled through the mouthpiece 25. A flow of air is generated through the device to the patient port 23 via a vent 67. By moving the wing 31 as described in Fig. 1, the member 35 temporarily closes the reed switch 65 so that the control mechanism 19 selectively activates the solenoid 61, causing the hammer 63 to impact the exposed carrier portion. The hammer impact on the carrier 57 releases respirable-sized medicament particles into the aerosolization chamber 11 where they are entrained in the developing air stream as the patient inhales.

In Fig. 3a, a front view of an inhaler with indirect breath actuation of an impact device is shown. A wing 85, explained later, is omitted to illustrate how the exposure frame 59, facing the patient by inserting the mouthpiece 25 into the oral cavity, forms the exposed surface of the elongate support 57. A percussion hammer 69 is held in an armed position by a lock 71 and released by detection of a flow of air through the device.

Fig. 3b shows a rear view of the inhaler of Fig. 3a and illustrates the position of ventilation openings 73, an arming arm 75 for the impact hammer and a dose advance lever 77 which is recessed in a slot 79.

Fig. 3c shows a top view of the inhaler of Fig. 3a.

Fig. 3d shows a section through the inhaler on the axis A-A. The inhaler comprises: a housing 1 with an extension 81 for indirect breathing actuation with integrated ventilation openings 73, the housing forming an aerosolization chamber 11 in connection with a patient connection 23 and the ventilation openings 73. The carrier 57 is wound on a spool 55. A carrier supply device is not shown, but would normally also be a spool.

The unexposed carrier 57 is sequentially advanced over the exposure frame 59 by the recessed lever 77 which drives a suitable gear train 83 which rotates the coil 55. The percussion hammer 59 is armed by the patient prior to inhalation by retracting the spring-loaded rod 75 until the catch 71 engages.

The vane 31 is displaceable when airflow is generated by patient inhalation through the device. The vane is spring loaded (not shown) to return to the displaceable home position when airflow stops. Displacement of the vane 31 interacts with the catch 71 to release the impact hammer 69. Hammer impact on the carrier 57 releases respirable-sized drug particles into the aerosolization chamber 11, whereupon they are entrained in the developing airflow as the patient inhales.

The wing 85 ensures a flow of air in one direction from the outside atmosphere via the ventilation openings 73 to the patient connection 23, as it can only be moved in a forward direction. A stop 43 prevents movement in a backward direction when the patient exhales.

In a variation (not shown), the wings 31 and 85 may be replaced by a single wing.

Referring to Figures 4a and 4b, an inhaler is shown with the integrated carrier supply reel 51, the take-up reel 55 and a brush/scraper device for aerosolization. The carrier 57 is advanced over a carrier support 87 into contact with a spring-operated or electrically driven (not shown) rotary brush 89.

Indirect respiratory actuation is provided by displacement of the wing 31 by a developing airflow as the patient inhales, which completes an electrical circuit containing a battery and motor (not shown) to drive the rotating brush 89, or alternatively allows a tensioned spring mechanism (not shown) to rotate the brush.

Fig. 5 shows an inhaler of a reusable form with a disposable cassette 91 with a portion of the housing and disposable cassette cut away. The cut away portion shows the relative position of the carrier supply reel 52 and carrier take-up reel 56 in the cassette to the gear train 83 which drives the carrier advance. When the cassette is inserted, spindles (only one spindle 52a for the supply reel is shown) engage the reels 52 and 56, respectively. A disposable inhaler can be made by replacing the cassette 91 with integral reels 51, 55 (not shown). The sequential advance of unused carrier 57 to the exposure frame 59 is accomplished by a recessed dose advance wheel 93 which engages the gear train 83 and rotates the take-up reel 56. A solenoid buzzer 17 is activated by closing a circuit containing a battery cell (not shown). This can be accomplished by incorporating a sliding vane (not shown) as described in Figs. 1 to 4. A vibrating head 41, which contacts the carrier at the exposure frame 59, causes the release of medication from the carrier where it can be entrained by the patient's inspiratory effort.

Claims (11)

1. Dry powder inhaler (1) with: a housing (3) which forms a chamber (11) for receiving a powdered dose of medication, a patient connection (23) in the form of a mouthpiece or nose adapter, an inhalation channel connected to the chamber and the patient connection, a deagglomerator (14, 41, 63, 89) that deagglomerates the powdered drug dose or helps to aerosolize it, an electrically operated device (17, 61) which drives the deagglomerator, a patient-independent energy output source (13) that drives the electrically operated device, a detector that detects the inspiration flow through the inhalation channel, and a controller for actuating the deagglomerator in response to detection of the inspiratory flow by the detector, characterized in that the detector has a movable vane positioned in the patient port or in the chamber, the vane being constructed and arranged to prevent exhaled air from reaching stored powdered medication. 2. The dry powder inhaler of claim 1, wherein the patient-independent power output source comprises a battery. 3. Dry powder inhaler according to claim 1, wherein the control comprises a mechanical coupling between the detector and deagglomerator. 4. A dry powder inhaler according to claim 3, wherein the control is a switch. 5. A dry powder inhaler according to any preceding claim, wherein the deagglomerator comprises means for impacting, striking or vibrating the dose of medicament. 6. A dry powder inhaler according to claim 5, wherein the means for impacting or striking comprises a magnetic coil. 7. Dry powder inhaler according to claim 5, wherein the device generates vibrations in the frequency range of 5 to 250,000 Hz and is electrical, piezoelectric, electromagnetic or mechanical. 8. A dry powder inhaler according to any one of claims 1 to 3, wherein the deagglomerator comprises a propeller or an impeller that generates a turbulent air flow that causes drug release. 9. A dry powder inhaler according to any preceding claim, wherein the powdered medicament is enclosed in a rupturable capsule and the inhaler is adapted to receive the capsule and comprises means for breaking the capsule. 10. A dry powder inhaler according to any preceding claim in combination with a powdered medicament having a particle size in the range 1 to 10 µm and comprising one or more drugs selected from bronchodilators, corticosteroids, anorectics, antidepressants, antihypertensives, antineoplastics, anticholinergics, dopaminergics, narcotic analgesics, adrenergic beta-blockers, prostaglandins, sympathomimetics, tranquilizers, steroids, proteins, peptides, vitamins, Sex hormones and asthma prophylactics are selected. 11. Dry powder inhaler according to claim 10, wherein the medicament is salbutamol, terbutaline, rimiterol, fentanyl, fenoterol, pirbuterol, reproterol, adrenaline, isoprenaline, ociprenaline, ipratropium, beclomethasone, betamethasone, budesonide, disodium cromoglycate, nedocromil sodium, ergotamine, salmeterol, fluticasone, Formoterol, insulin, atropine, prednisolone, benzphetamine, chlorphentermine, amitriptyline, imipramine, cloridine, actinomycin C, bromocriptine, buprenorphine, propranolol, lacicortone, hydrocortisone, fluocinolone, triamcinclone, dinoprost, xylometazoline, diazepam, lorazepam, Folic acid, nicotinamide, clenbuterol, bitolterol, ethinyloestradiol and levenorgestrel and their pharmaceutically acceptable salts.